The broad objective of this program project grant is to gain further insight into the biochemistry of aging by examining the integrity of a diverse, select group of regulatory mechanisms. One project concerns the relative contribution by beta cells and by other cell types within isolated pancreatic islets of Langerhans to the previously reported inability of isolated islets from aged Sprague-Dawley rats to secrete insulin in response to glucose. Availability and/or action of somatostatin, glucagon and other islet secretory products are being studied with respect to glucose-stimulated secretion of insulin. A second project concerns the capacity of cultured fibroblasts from mammalian species of different lifespans to activate polycyclic hydrocarbon carcinogens. The regulatory role of mixed function oxidases, the relationship to general drug-metabolizing activity, and the binding of active metabolites to DNA are being studies in several cellular systems. A third project concerns the role of dehydroepiandrosterone (DHEA) in apparently delaying the rate of aging, as well as inhibiting spontaneous breast cancer in female mice. Long term effects of DHEA are being examined with respect to development of autoimmunity and such related processes as the appearance of Coombs positive hemolytic anemia, DNA antibodies, and renal histopathology.